1. Field of the Invention
The present invention concerns treating patients suffering from adverse habits or cravings by administering a pharmaceutically active compound, which compound results in activation of a brain reward system, e.g., flupenthixol (also called "flupentixol").
2. Background Information
Habit disorders have a substantial consequence for health. The course of various habit disorders may be positively affected by therapeutic psychopharmacological agents that influence the nervous system. The commonality between various habit disorders is a neurophysiological state expressed by the craving or desire for the habit.
One of the most problematic and prototypal examples of a habit disorder is "crack" cocaine smoking. "Crack" cocaine smoking has now produced epidemic cocaine dependence in the urban United States, following earlier epidemic abuse in the Bahamas (Jekel, J. F., Allen, D. F., Podlewski, H., Clarke, N., Dean-Patterson, S., Cartwright, P., "Epidemic Cocaine Free-Base Abuse: Case Study from the Bahamas", Lancet, (1986), 1, 459-462).
Cocaine smoking and intravenous cocaine injection are equi-potent in their central effects and in their abuse liability (Gawin, F. H., Ellinwood, E. H., "Cocaine and Other Stimulants; Actions, Abuse, and Treatment", New Engl. J. Med., (1988), 318, 1173-1182 and Gawin, F. H., Kleber, H. D., "Evolving Conceptualizations of Cocaine Dependence", Yale J. Biol. Med., (1988), 123-136).
"Crack" is defined as cocaine distributed in ready-to-smoke form (cocaine free base), rather than as the injectable or insufflatable cocaine hydrochloride. Previously, cocaine smoking ("freebasing") required a complex extraction by the end user, of free cocaine base from cocaine hydrochloride, limiting the availability and thus the extent of cocaine dependence by smoking (Gawin and Ellinwood, supra).
"Crack" is generally sold in small, inexpensive one or two inhalation quantities, in a marketing system that, in contrast to prior cocaine distribution, saturates a region with ubiquitous "street" cocaine distributors. The combination of low initial expense, unprecedented availability, and extreme abuse liability has resulted in an epidemic of refractory, recurrent cocaine dependence, making obvious the limits of current cocaine abuse treatment strategies for "Crack" abuse, and has lead to unprecedented levels of public concern.
Cocaine withdrawal is characterized by a protracted anhedonic dysphoria (Gawin, F. H., Kleber, H. D., "Abstinence Symptomatology and Psychiatric Diagnosis in Chronic Cocaine Abusers", Arch. Gen. Psychiatry, (1986), 43, 107-113) that produces craving for cocaine (Jekel et al, supra). Episodically superimposed on this craving is an additional pulsatile craving produced by exposure to conditioned cues (independent stimuli present during past episodes of cocaine euphoria) (Jekel et al, supra). Such cues evoke vivid memories of extreme cocaine euphoria. The likelihood of continued cocaine smoking in an abuser is related to the strength of the craving experienced from these two sources.
In "crack" abuse, the withdrawal dysphoria is combined with ubiquitous cocaine sales and availability, and hence ubiquitous presence of conditioned cues, to produce an intractable abuse that has been considered, by many, to be impossible to treat without hospitalization, (Jekel et al, supra and Grabowski, J., Dworkin, S. I., "Cocaine: An Overview of Current Issues, Int. J. Addict, (1985), 20, 1065-88). Unfortunately, the crack epidemic has appeared in impoverished populations with very limited access to inpatient resources.
Prior outpatient pharmacotherapy trials for cocaine dependence demonstrate that high-dose heterocyclic antidepressants are effective in reversing cocaine withdrawal craving, but that their efficacy is delayed by 10-14 days from the outset of therapy (Giannini, A. J., Malone, D. A., Giannini, M. C., Price, W. A., Loiselle, R. H., "Treatment of Depression in Chronic Cocaine and Phencyclidine Abuse with Desipramine", J. Clin. Pharmacol., (1986), 26, 211-4 and Gawin, F. H., Kleber, H. D., Byck, R., Rounsaville, B., Kosten, T. R., Jatlow, P., Morgan, C., "Desipramine Facilitation of Initial Cocaine Abstinence", Arch. Gen. Psychiatry, (1989) Arch. Gen. Psychiatry, 46, 117-121. In outpatient "crack" smokers, the extreme availability of the drug often results in resumption of cocaine smoking early in treatment, producing non-compliance to voluntary oral medication regimens that usually results in cessation of all forms of treatment, including psychotherapy, before the possible onset of any therapeutic medication effects (Gawin, Kleber, Byck, Rounsaville, Kosten, Jatlow and Morgan, supra). In this context, a depot preparation or more rapidly acting agent would have advantages over other methods of medication administration.
Flupenthixol decanoate is a depot xanthene derivative with unique properties, having both rapid antidepressant activity at low doses (Poldinger, W., Sieberns, S., "Depression-inducing and Antidepressive Effects of Neuroleptics: Experiences with Flupenthixol and Flupenthixol Deanoate", Neuropsychobiology, (1983), 10, 131-136 and Robertson. M. M., Trimble, M. R., (1982), "Major Tranquilizers Used as Antidepressants", J. Affective Dis., 4, 173-195) and neuroleptic activity at higher doses (Trueman, H. R., Valentine, M. G., (1974), "Flupenthixol Decanoate In Schizophrenia", Br. J. Psychiatry, 124, 58-59).
Flupenthioxil appears to act by blocking dopamine binding to a number of receptors, including D-1, D-2, and inhibitory D-2 autoreceptors.
Although classified as a neuroleptic, and not as a typical antidepressant, low dose flupenthixol has been established as being as effective as conventional heterocyclic antidepressants in over fifteen double-bind controlled trials (Valle-Jones, J. C. and Swarbrick, D. J., (1981), A Comparative Study of Once-daily Flupenthixol in the Treatment of Elderly Depressed Patients: A Multicentre Trial in General Practice, Curr. Med. Res. Opin., 7, 543-549; Wheatley, D. P., (1983), "Antidepressant Effect of Flupenthixol Compared to Miaserin", J. Int. Biomet. Inform. Data., 4, 5-12; Young, J. P. P., Hughes, W. C. and Lader, M. H., (1976), "A Controlled Comparison of Flupenthixol and Amitriptyline in Depressed Out-Patients", Br. Med. J., 1, 1116-1118; Johnson, D. A. W., (1979), "A Double-blind Comparison of Flupenthixol, Nortriptyline and Diazepam in Neurotic Depression", Acta. Psychiatr. Scand., 59, 1-8; Presdescu, V., Ciurezu, T., Timofte, G. and Roman, I., (1973), "Symptomatic Relief with Flupenthixol (Fluanxol) of the Anxious- Algetic-Depressive Syndrome Complex in Neurotic States", Acta Psychiat. Scand., 49, 15-27; Frolund, F., (1974), "Treatment of Depression in General Practice. A Controlled Trial of Flupenthixol", Curr. Med. Res. Opin., 2, 78-89; Ovhed, I., (1976), A double-blind Study of Flupenthixol (`Fluanxol`) in General Practice", Curr. Med. Res. Opin., 4, 144; Rosenberg, I. U., Ostensen, A. I., and Fonnelop, H., "Flupenthixol- nortriptyline in the Treatment of Patients with Anxiety- Depression-Asthenia (the `ADA syndrome`)" (translation). Tidsskr. Norske. Laegeforen., 96, 229-233; Sederberg-Olsen, A. P., Lauritsen, B., Husfeldt, P., Ronne, H., Ekstrome, K., Bjorndal, F., Holst, B. and Jakobsen, K., (1979), "Depressive Tilstande, Forekomst og Behandling i Almen Praksis", Ugeskr. Laeg., 143, 1383-1387; Wheatley, D. P., (1983), "Antidepressant Effects of Flupenthixol Compared to Mianserin. A report from the Psychopharmacology Branch of the General Practitioner Research Group", Int. Biomed. Inf. Data., 4, Suppl. 1, 5-12; Razak, J. (unpubl. report, 1983), "Flupenthixol Versus Phenelzine in the Treatment of Neurotic Depression: A Double-Blind Trial"; Conway, J. F., (1981), "Flupenthixol Versus Combined Fluphenazine-Nortriptyline in Depressive Illness", Practitioner, 225, 400-404; Simmelsgaard, H., Frankel, I., Gunner-Svensson, F., Poulsen, H., Blumenthal, M., Metsa-Simola, S., Grohn, P., Reinertsen, T., Schmidt, P., Brandrup, E. and Sovso, H., (1973), "Multicentre Double-Blind Clinical Trial of Flupenthixol (Fluanxol) and Flupenthixol+Medlitracen (Lu 6722) in the Treatment of Neuroses", (translation), Nord. Psyckiat. Tidsskr., 27, 145-54; Baldwin, R., Cranfield, R., Swarbrick, D. J., (1983), "A Double-Blind Trial Comparing Single and Divided Daily Doses of Flupenthixol in the Treatment of Mild to Moderately Severe Depression". A Multicentre Trial in General Practice", J. Int. Biomet. Inform. Data, 4, 37-42; Majiid, I., Swarbrick, D. J., (1983), "A Double-Blind Comparison of a Single Daily Dose of 1 mg or 2 mg flupenthixol Dihydrochloride in the Treatment of Depression", J. Int. Biomet.Inform. Data, 4, 13-17; Valle-Jones, J. C., Swarbrick, D. J., (1983), "A Comparative Study of Once Daily Flupenthixol and Amitriptyline in the Treatment of Elderly Depressed Patients: A Multicentre Trial in General Practice", J. Int. Biomet. Inform. Data, 4, 29-35 and Tam, W., Young, J. P. R., John, G. and Lader, M. H., (1982), A Controlled Comparison of Flupenthixol Decanoate Injections and Oral Amitriptyline in Depressed Out-Patients", Br. J. Psychiatry, 140, 287-291). Thus, similar to antidepressants, flupenthixol might positively influence the outcome of the treatment of the habit disorder.
Both habit forming activities (e.g., feeding) and ingestion of abused substances increase neural activity in regions of the brain that produce rewarding feelings. Different habit disorders or "addictions" have been hypothesized to be similar in that a final common pathway for their compelling properties is activation of reward systems (Wise, R. A. and Bozarth, M. A., "A Psychometer Stimulant Theory of Addiction", Psychological Review, 94, 469-472, (1987); Wise, R., "Neural Mechanisms of the Reinforcing Action of Cocaine", (1984), NIDA Res. Mon. Series, Vol. 50, U.S. Government Printing Office, Washington, D.C., pp. 15-53).
It has also been hypothesized that many chronic habit disorders (e.g., stimulant abuse and other abuses) produce compensatory adaptations in brain reward systems that produces decreased reward activity, and thus craving and other symptoms that emerge in the absence of the habitual activity. It is hypothesized that this craving is induced by decreases in dopaminergic activity, mediated by supersensitivity of inhibitory dopaminergic auto-receptors, (Gawin and Ellinwood, New Eng. J. Med., (1988), 318, 1173-1182). Auto-receptor supersensitity has recently been demonstrated experimentally in animals exposed to chronic cocaine (Dwoskin, L. P., Peris, J., Yasuda, R. P., Philpott, K., Zahniser, N. R., "Repeated Cocaine Administration Results in Supersensitivity of Striatal D-2 Dopamine Autoreceptors to pergolide", Life Sci., (1988), 42, 255-262). Similar changes may mediate cravings for other habits.
Without wishing to be bound by any particular theory of operability it is believed that a low concentration of flupenthixol may demonstrate greater affinity for dopamine auto-receptors than post-synaptic receptors, and preferentially bind to these inhibitory sites, suggesting that increased dopaminergic activity, and anti-anhedonic, anti-depressant activity would follow application of low flupenthixol doses, decreasing craving for a habit. At higher dosages and plasma concentrations, as effects on post-synaptic D-1 and D-2 receptors predominate, cocaine blocking and anhedonia inducing activity might occur.
Clinically acceptable concentrations of conventional phenothiazine or butyrophenone neuroleptics may exacerbate anhedonic stimulant withdrawal symptoms (Wise et al, supra and Gawin, F. H., "Neuroleptic Reduction of Cocaine Induced Paranoia but Not Euphoria", Psychopharmacology, (1986), 90, 142-143) in cocaine abusers resulting in an extreme patient resistance to neuroleptic treatment.
Significantly, low dose flupenthixol has been demonstrated to lack the anhedonia-inducing effects of similar agents in animal models (Ettenburg, A., Koob, G. F., Bloom, F., "Response Artifact in Measurement of Neuroleptic-induced Anhedonia", Science, (1981), 213, 237-239), and to lack characteristic neuroleptic-like behavioral effect in humans (Mattila, M. J., Mattila, M., Aranko, K., "Objective and Subjective Assessments of the Effects of Flupenthixol and Benzodiazepines on Human Psychomotor Performance", Psychchopharmacology, (1988), 95, 323-328).